UNAIDS estimates approximately 2.3 million new HIV infections in 2012, indicating an ongoing need for prevention of HIV infection. Men who have sex with men (MSM) are the group at highest risk of HIV acquisition through unprotected receptive anal intercourse (URAI) and are an important part of the epidemic in both developed and low and middle income countries. MSM remain the majority of the U.S. epidemic where most incident infections are among MSM (63% overall and 78% among men). These men also serve as a source of HIV infection for other risk groups. In Baltimore neighborhoods, 38% of MSM have HIV infection with seroincidence rates of 11% in young African American MSM. In a survey of U.S. MSM, 36% reported having RAI at last sex, and the percentage who reported not using condoms ranged from 38-65%. Women globally also engage in anal intercourse at 10-20% levels, substantial given their percent of the population, and report lower condom use than most MSM surveys. The combination of high RAI frequency, low condom use, and higher risk of HIV infection via RAI argues strongly for strategies to prevent HIV infection associated with URAI.
Pre-exposure prophylaxis (PrEP) with the NRTI tenofovir (TFV)-based drug regimens has been tested in 6 randomized controlled trials (RCTs) and demonstrates a clear plasma concentration-HIV protection response among studies. In iPrEx, the only study targeting MSM, daily oral TFV disoproxil fumarate (TDF)/emtricitabine (FTC) provided 92% protection with evidence of only 2 doses per week (measurable plasma TFV) whereas heterosexual studies indicated similar protection only with 6-7 doses per week.
Reports of enema use before sex by MSM range widely: 51-96% in New York City, 67% in Baltimore, 18-53% in African-Americans, and 28% in Peru. Typically, enemas were taken within 2 hours before and 1 hour after sex (when enemas are used less often) for reasons of hygiene, partner desire, and belief in HIV protection. Several MSM studies indicate between 80% and 100% willingness to use rectal microbicide enemas, especially in the absence of condoms.
A number of formulations have been tested for this purpose, for example, in prior IP/CP U19 programs, MDP (Anton, PI) and CHARM (McGowan, PI). For example, RMP-02/MTN-006 studied rectal application of VF (vaginal formulation) TFV 1% gel (used in CAPRISA 004 and VOICE), a very hyperosmolar formulation compared to RF (rectal optimized formulation, developed in MDP) and RGVF (reduced glycerin vaginal formulation, developed in MTN). RMP-02/MTN-006 demonstrated that VF applied rectally was associated with gastrointestinal-related Grade 3 adverse events (only during 7-day exposure) and less than desired acceptability. Another MDP study and a CDC funded study also demonstrated mucosal tissue abnormalities with hyperosmolar enemas and gels, respectively.
The rectal columnar epithelium is fragile and extremely vulnerable to HIV-1 infection, in part due to the proximity of sub-epithelial stromal tissues that are densely populated with cells receptive to incident HIV-1 infection, such as dendritic cells (DCs), macrophages and T-cells that express both CD4 and both HIV-1 co-receptors CCR5 and CXCR4. Although the mechanisms of viral uptake and infection across rectal mucosa are not fully established, such physiological and anatomical differences may explain why HIV is more readily transmitted across rectal than across the cervicovaginal genital epithelium. In conjunction with this higher transmission risk of rectal versus vaginal exposure to HIV, there is a higher concentration of tenofovir achievable in colonic tissue than in vaginal tissue. The plasma concentration of tenofovir associated with 90% protection (EC90) in PK/PD models, 107 ng/mL, was not achieved by the most highly adherent heterosexual subpopulations. Achievement of concentrations above 107 ng/mL requires fastidious adherence and daily dosing. This is in contrast to the protective effect for MSM which is achieved with only 2 to 4 doses of oral TFV per week.
Given the (1) very high efficacy of TFV-based PrEP, (2) more efficient delivery of active drug to the colon with rectal compared to oral dosing, (3) the large negative impact of poor adherence on PrEP outcomes, (4) frequency of URAI in men and women, and (5) the common pre-existing behavior of enemas use before and after RAI by many MSM, there exists an unmet need for the development of a pharmacokinetically-enhanced TFV prodrug enema capable of protecting subjects from HIV acquisition.
It is therefore an object of the present invention to provide formulations for administration rectally to deliver an effective amount of antimicrobial, especially antiviral, to reduce the likelihood of HIV infection.
It is a further object of the present invention to provide such formulations which are safe, comfortable and easy to store and use.